Serum levels of cholesterol and atherosclerosis are significant topics addressed by health care professionals as they relate to cardiac disease, as well as other circulatory and systemic diseases. There is a great interest in the medical field with regard to the reduction of serum cholesterol and the reversal of an atherosclerotic condition.
Various means have been used in an attempt to lower serum cholesterol. For example, various resins have been administered therapeutically to sequester bile acids and thereby reduce systemic cholesterol levels. Other therapeutics have been administered in an attempt to effect cholesterol metabolism. However, there remains a high level of interest and need for more effective therapeutics in this area.
Serum amyloid A (SAA) is an apolipoprotein which is present on high density lipoprotein (HDL) only during inflammatory states. SAA was discovered approximately 15 years ago in the course of studies examining serum for potential precursors to the inflammation-associated AA form of amyloid. It has been determined that the AA peptide responsible for the inflammation-associated amyloid fibril represented a fragment of the SAA protein (1,2). Based on amino acid sequencing of SAA in the preparation, cloning, and identification of genes possessing the information for this protein (1,3), it became apparent that SAA was not a single protein, but rather a family of several related proteins. Work with these proteins have shown that during an inflammatory reaction, the cytokines interleukin-1, interleukin-6 and tumor necrosis factor are responsible for regulating the transcription of the SAA gene in liver (4,5). Recent studies have suggested that SAA has a significant influence on lecithin cholesterol acyl transferase activity associated with the HDL (6).
It is well established that SAA is present in the circulation in substantial quantities only during inflammation. Ninety percent (90%) or more of the SAA is associated with HDL's. HDL is also well established in the function of reverse cholesterol transport (7).
With specific regard to atherosclerosis, observations in the early twentieth century in patients who had long standing infections or malignancies showed that these patients at the time of death had far less atherosclerosis, or had the equivalent of "healed" atherosclerosis, when compared to patients of equivalent age who did not have these preceding disorders. This observation was always attributed to the patient's debilitated physical state or that their nutritional state was inadequate when compared to healthy individuals of the same age.
Based on the above compiled observations, and based on studies observing the potential roles of SAA's as a signal to HDL's, the present invention provides means for potentiating the efflux of macrophage cholesterol, thereby providing a means for therapeutically reducing cholesterol at atherosclerotic sites. This potentiating effect should lead to reversal of an atherosclerotic condition.